Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, 17121 Solna, Sweden.
Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, 17121 Solna, Sweden.
J Phys Chem B. 2024 May 23;128(20):4996-5007. doi: 10.1021/acs.jpcb.4c01703. Epub 2024 May 15.
Glycine receptors are pentameric ligand-gated ion channels that conduct chloride ions across postsynaptic membranes to facilitate fast inhibitory neurotransmission. In addition to gating by the glycine agonist, interactions with lipids and other compounds in the surrounding membrane environment modulate their function, but molecular details of these interactions remain unclear, in particular, for cholesterol. Here, we report coarse-grained simulations in a model neuronal membrane for three zebrafish glycine receptor structures representing apparent resting, open, and desensitized states. We then converted the systems to all-atom models to examine detailed lipid interactions. Cholesterol bound to the receptor at an outer-leaflet intersubunit site, with a preference for the open and desensitized versus resting states, indicating that it can bias receptor function. Finally, we used short atomistic simulations and iterative amino acid perturbations to identify residues that may mediate allosteric gating transitions. Frequent cholesterol contacts in atomistic simulations clustered with residues identified by perturbation analysis and overlapped with mutations influencing channel function and pathology. Cholesterol binding at this site was also observed in a recently reported pig heteromeric glycine receptor. These results indicate state-dependent lipid interactions relevant to allosteric transitions of glycine receptors, including specific amino acid contacts applicable to biophysical modeling and pharmaceutical design.
甘氨酸受体是五聚体配体门控离子通道，可在突触后膜上传导氯离子，促进快速抑制性神经传递。除了甘氨酸激动剂的门控作用外，与周围膜环境中的脂质和其他化合物的相互作用也调节其功能，但这些相互作用的分子细节仍不清楚，特别是对于胆固醇。在这里，我们报告了三种斑马鱼甘氨酸受体结构的粗粒化模拟，代表了明显的静息、开放和脱敏状态。然后，我们将系统转换为全原子模型，以检查详细的脂质相互作用。胆固醇与受体在外部小叶亚基间位点结合，对开放和脱敏状态相对于静息状态具有偏好性，表明它可以偏向受体功能。最后，我们使用短原子模拟和迭代氨基酸扰动来确定可能介导变构门控跃迁的残基。原子模拟中频繁的胆固醇接触与扰动分析确定的残基聚集在一起，并与影响通道功能和病理学的突变重叠。在最近报道的猪杂合甘氨酸受体中也观察到了该位点的胆固醇结合。这些结果表明，与甘氨酸受体的变构跃迁相关的脂质相互作用具有状态依赖性，包括适用于生物物理建模和药物设计的特定氨基酸接触。
